bupropion hydrochloride 100 MG 12 HR Extended Release Oral Tablet
WARNINGS
Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders: Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.
Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.
There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.
Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders.
Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 patients.
The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.
There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied.
There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD.
The risk differences (drug vs.
placebo), however, were relatively stable within age strata and across indications.
These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1.
Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials.
There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.
However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers.
Such monitoring should include daily observation by families and caregivers.
Prescriptions for bupropion hydrochloride extended-release tablets (SR) should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment: Wellbutrin®*, bupropion hydrochloride extended-release tablets (SR), and Wellbutrin XL®*are not approved for smoking cessation treatment, but bupropion under the name Zyban®* is approved for this use.
Serious neuropsychiatric symptoms have been reported in patients taking bupropion for smoking cessation (see BOXED WARNING, ADVERSE REACTIONS).
These have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide.
Some reported cases may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking.
Depressed mood may be a symptom of nicotine withdrawal.
Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication.
However, some of these symptoms have occurred in patients taking bupropion who continued to smoke.
When symptoms were reported, most were during bupropion treatment, but some were following discontinuation of bupropion therapy.
These events have occurred in patients with and without pre-existing psychiatric disease; some have experienced worsening of their psychiatric illnesses.
All patients being treated with bupropion as part of smoking cessation treatment should be observed for neuropsychiatric symptoms or worsening of pre-existing psychiatric illness.
Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major depressive disorder did not participate in the pre-marketing studies of Zyban®*.
Advise patients and caregivers that the patient using bupropion for smoking cessation should stop taking bupropion and contact a healthcare provider immediately if agitation, depressed mood, or changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior.
In many postmarketing cases, resolution of symptoms after discontinuation of Zyban®* was reported, although in some cases the symptoms persisted, therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.
The risks of using bupropion for smoking cessation should be weighed against the benefits of its use.
Zyban®*has been demonstrated to increase the likelihood of abstinence from smoking for as long as six months compared to treatment with placebo.
The health benefits of quitting smoking are immediate and substantial.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder.
It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder.
Whether any of the symptoms described above represent such a conversion is unknown.
However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.
It should be noted that bupropion hydrochloride extended-release tablets (SR) are not approved for use in treating bipolar depression.
Bupropion-Containing Products: Patients should be made aware that bupropion hydrochloride extended-release tablets (SR) contain the same active ingredient found in Zyban ®* , used as an aid to smoking cessation treatment, and that bupropion hydrochloride extended-release tablets should not be used in combination with Zyban ®* , or any other medications that contain bupropion, such as Wellbutrin ®* (bupropion hydrochloride), the immediate-release formulation or Wellbutrin XL ®* (bupropion hydrochloride), the extended-release formulation.
Seizures: Bupropion is associated with a dose-related risk of seizures.
The risk of seizures is also related to patient factors, clinical situations, and concomitant medications, which must be considered in selection of patients for therapy with bupropion hydrochloride extendedrelease tablets (SR).
Bupropion hydrochloride extended-release tablets (SR) should be discontinued and not restarted in patients who experience a seizure while on treatment.
Dose: At doses of sustained-release bupropion up to a dose of 300 mg/day, the incidence of seizure is approximately 0.1% (1/1,000) and increases to approximately 0.4% (4/1,000) at the maximum recommended dose of 400 mg/day.
Data for the immediate-release formulation of bupropion revealed a seizure incidence of approximately 0.4% (i.e., 13 of 3,200 patients followed prospectively) in patients treated at doses in a range of 300 to 450 mg/day.
The 450 mg/day upper limit of this dose range is close to the currently recommended maximum dose of 400 mg/day for bupropion hydrochloride extended-release tablets (SR).
This seizure incidence (0.4%) may exceed that of other marketed antidepressants and bupropion hydrochloride extended-release tablets (SR) up to 300 mg/day by as much as 4-fold.
This relative risk is only an approximate estimate because no direct comparative studies have been conducted.
Additional data accumulated for the immediate-release formulation of bupropion suggested that the estimated seizure incidence increases almost tenfold between 450 and 600 mg/day, which is twice the usual adult dose and one and one-half the maximum recommended daily dose (400 mg) of bupropion hydrochloride extended-release tablets (SR).
This disproportionate increase in seizure incidence with dose incrementation calls for caution in dosing.
Data for bupropion hydrochloride extended-release tablets (SR) revealed a seizure incidence of approximately 0.1% (i.e., 3 of 3,100 patients followed prospectively) in patients treated at doses in a range of 100 to 300 mg/day.
It is not possible to know if the lower seizure incidence observed in this study involving the sustained-release formulation of bupropion resulted from the different formulation or the lower dose used.
However, as noted above, the immediate-release and sustained-release formulations are bioequivalent with regard to both rate and extent of absorption during steady state (the most pertinent condition to estimating seizure incidence), since most observed seizures occur under steady-state conditions.
Patient factors: Predisposing factors that may increase the risk of seizure with bupropion use include history of head trauma or prior seizure, central nervous system (CNS) tumor, the presence of severe hepatic cirrhosis, and concomitant medications that lower seizure threshold.
Clinical situations: Circumstances associated with an increased seizure risk include, among others, excessive use of alcohol or sedatives (including benzodiazepines); addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; and diabetes treated with oral hypoglycemics or insulin.
Concomitant medications: Many medications (e.g., antipsychotics, antidepressants, theophylline, systemic steroids) are known to lower seizure threshold.
Recommendations for Reducing the Risk of Seizure: Retrospective analysis of clinical experience gained during the development of bupropion suggests that the risk of seizure may be minimized if the total daily dose of bupropion hydrochloride extended-release tablets (SR) does not exceed 400 mg, the daily dose is administered twice daily, and the rate of incrementation of dose is gradual.
No single dose should exceed 200 mg to avoid high peak concentrations of bupropion and/or its metabolites.
Bupropion hydrochloride extended-release tablets (SR) should be administered with extreme caution to patients with a history of seizure, cranial trauma, or other predisposition(s) toward seizure, or patients treated with other agents (e.g., antipsychotics, other antidepressants, theophylline, systemic steroids, etc.) that lower seizure threshold.
Hepatic Impairment: Bupropion hydrochloride extended-release tablets (SR) should be used with extreme caution in patients with severe hepatic cirrhosis.
In these patients a reduced frequency and/or dose is required, as peak bupropion, as well as AUC, levels are substantially increased and accumulation is likely to occur in such patients to a greater extent than usual.
The dose should not exceed 100 mg every day or 150 mg every other day in these patients (see CLINICAL PHARMACOLOGY , PRECAUTIONS , and DOSAGE AND ADMINISTRATION ).
Potential for Hepatotoxicity: In rats receiving large doses of bupropion chronically, there was an increase in incidence of hepatic hyperplastic nodules and hepatocellular hypertrophy.
In dogs receiving large doses of bupropion chronically, various histologic changes were seen in the liver, and laboratory tests suggesting mild hepatocellular injury were noted.
DRUG INTERACTIONS
Drug Interactions: Few systemic data have been collected on the metabolism of bupropion following concomitant administration with other drugs or, alternatively, the effect of concomitant administration of bupropion on the metabolism of other drugs.
Because bupropion is extensively metabolized, the coadministration of other drugs may affect its clinical activity.
In vitro studies indicate that bupropion is primarily metabolized to hydroxybupropion by the CYP2B6 isoenzyme.
Therefore, the potential exists for a drug interaction between bupropion and drugs that are substrates of or inhibitors/inducers of the CYP2B6 isoenzyme (e.g., orphenadrine, thiotepa, cyclophosphamide, ticlopidine, and clopidogrel).
In addition, in vitro studies suggest that paroxetine, sertraline, norfluoxetine, and fluvoxamine as well as nelfinavir and efavirenz inhibit the hydroxylation of bupropion.
No clinical studies have been performed to evaluate this finding.
The threohydrobupropion metabolite of bupropion does not appear to be produced by the cytochrome P450 isoenzymes.
The effects of concomitant administration of cimetidine on the pharmacokinetics of bupropion and its active metabolites were studied in 24 healthy young male volunteers.
Following oral administration of two 150 mg bupropion hydrochloride extended-release tablets (SR) with and without 800 mg of cimetidine, the pharmacokinetics of bupropion and hydroxybupropion were unaffected.
However, there were 16% and 32% increases in the AUC and C max , respectively, of the combined moieties of threohydrobupropion and erythrohydrobupropion.
In a series of studies in healthy volunteers, ritonavir (100 mg twice daily or 600 mg twice daily) or ritonavir 100 mg plus lopinavir (KALETRA) 400 mg twice daily reduced the exposure of bupropion and its major metabolites in a dose dependent manner by approximately 20% to 80%.
This effect is thought to be due to the induction of bupropion metabolism.
Patients receiving ritonavir may need increased doses of bupropion, but the maximum recommended dose of bupropion should not be exceeded (see CLINICAL PHARMACOLOGY: Metabolism ).
While not systematically studied, certain drugs may induce the metabolism of bupropion (e.g., carbamazepine, phenobarbital, phenytoin).
Multiple oral doses of bupropion had no statistically significant effects on the single dose pharmacokinetics of lamotrigine in 12 healthy volunteers.
Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in humans.
In one study, following chronic administration of bupropion, 100 mg 3 times daily to 8 healthy male volunteers for 14 days, there was no evidence of induction of its own metabolism.
Nevertheless, there may be the potential for clinically important alterations of blood levels of coadministered drugs.
Drugs Metabolized By Cytochrome P450IID6 (CYP2D6): Many drugs, including most antidepressants (SSRIs, many tricyclics), beta-blockers, antiarrhythmics, and antipsychotics are metabolized by the CYP2D6 isoenzyme.
Although bupropion is not metabolized by this isoenzyme, bupropion and hydroxybupropion are inhibitors of CYP2D6 isoenzyme in vitro .
In a study of 15 male subjects (ages 19 to 35 years) who were extensive metabolizers of the CYP2D6 isoenzyme, daily doses of bupropion given as 150 mg twice daily followed by a single dose of 50 mg desipramine increased the C max , AUC, and t ½ of desipramine by an average of approximately 2-, 5-, and 2-fold, respectively.
The effect was present for at least 7 days after the last dose of bupropion.
Concomitant use of bupropion with other drugs metabolized by CYP2D6 has not been formally studied.
Therefore, coadministration of bupropion with drugs that are metabolized by CYP2D6 isoenzyme including certain antidepressants (e.g., nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be approached with caution and should be initiated at the lower end of the dose range of the concomitant medication.
If bupropion is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need to decrease the dose of the original medication should be considered, particularly for those concomitant medications with a narrow therapeutic index.
Although citalopram is not primarily metabolized by CYP2D6, in one study bupropion increased the C max and AUC of citalopram by 30% and 40%, respectively.
Citalopram did not affect the pharmacokinetics of bupropion and its three metabolites.
MAO Inhibitors: Studies in animals demonstrate that the acute toxicity of bupropion is enhanced by the MAO inhibitor phenelzine (see CONTRAINDICATIONS ).
Levodopa and Amantadine: Limited clinical data suggest a higher incidence of adverse experiences in patients receiving bupropion concurrently with either levodopa or amantadine.
Administration of bupropion hydrochloride extended-release tablets (SR) to patients receiving either levodopa or amantadine concurrently should be undertaken with caution, using small initial doses and gradual dose increases.
Drugs That Lower Seizure Threshold: Concurrent administration of bupropion hydrochloride extended-release tablets (SR) and agents (e.g., antipsychotics, other antidepressants, theophylline, systemic steroids, etc.) that lower seizure threshold should be undertaken only with extreme caution (see WARNINGS ).
Low initial dosing and gradual dose increases should be employed.
Nicotine Transdermal System: (see PRECAUTIONS: Cardiovascular Effects ).
Alcohol: In postmarketing experience, there have been rare reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol during treatment with bupropion extended-release tablets (SR).
The consumption of alcohol during treatment with bupropion extended-release tablets (SR) should be minimized or avoided (also see CONTRAINDICATIONS ).
OVERDOSAGE
Human Overdose Experience: Overdoses of up to 30 g or more of bupropion have been reported.
Seizure was reported in approximately one-third of all cases.
Other serious reactions reported with overdoses of bupropion alone included hallucinations, loss of consciousness, sinus tachycardia, and ECG changes such as conduction disturbances (including QRS prolongation) or arrhythmias.
Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported mainly when bupropion was part of multiple drug overdoses.
Although most patients recovered without sequelae, deaths associated with overdoses of bupropion alone have been reported in patients ingesting large doses of the drug.
Multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported in these patients.
Overdosage Management: Ensure an adequate airway, oxygenation, and ventilation.
Monitor cardiac rhythm and vital signs.
EEG monitoring is also recommended for the first 48 hours post-ingestion.
General supportive and symptomatic measures are also recommended.
Induction of emesis is not recommended.
Activated charcoal should be administered.
There is no experience with the use of forced diuresis, dialysis, hemoperfusion, or exchange transfusion in the management of bupropion overdoses.
No specific antidotes for bupropion are known.
Due to the dose-related risk of seizures with bupropion hydrochloride extended-release tablets (SR), hospitalization following suspected overdose should be considered.
Based on studies in animals, it is recommended that seizures be treated with intravenous benzodiazepine administration and other supportive measures, as appropriate.
In managing overdosage, consider the possibility of multiple drug involvement.
The physician should consider contacting a poison control center for additional information on the treatment of any overdose.
Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR).
DESCRIPTION
Bupropion hydrochloride extended-release tablets (SR), an antidepressant of the aminoketone class, are chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other known antidepressant agents.
Its structure closely resembles that of diethylpropion; it is related to phenylethylamines.
It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1- dimethylethyl)amino]-1 -propanone hydrochloride.
The molecular weight is 276.2.
The molecular formula is C 13 H 18 ClNO•HCl.
Bupropion hydrochloride powder is white, crystalline, and highly soluble in water.
It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa.
The structural formula is: Bupropion hydrochloride extended-release tablets (SR) are supplied for oral administration as 100 mg, 150 mg, and 200 mg white to off-white, film-coated, extended-release tablets.
Each tablet contains the labeled amount of bupropion hydrochloride and the following inactive ingredients: hydroxypropyl cellulose, microcrystalline cellulose, colloidal silicon dioxide, stearic acid, magnesium stearate, and diluted hydrochloric acid.
The film coating contains lactose monohydrate, hydroxypropyl cellulose, titanium dioxide, and polyethylene glycol.
20ba0ead-figure-01
HOW SUPPLIED
Bupropion hydrochloride extended-release tablets (SR), 100 mg of bupropion hydrochloride, are white to off-white, round, film-coated tablets with WPI over 858 in bottles of 60 tablets (NDC 0591-3540-60).
Bupropion hydrochloride extended-release tablets (SR), 150 mg of bupropion hydrochloride, are white to off-white, round, film-coated tablets with WPI over 839 in bottles of 60 tablets (NDC 0591-3541-60) and 250 tablets (NDC 0591-3541-25).
Bupropion hydrochloride extended-release tablets (SR), 200 mg of bupropion hydrochloride, are white to off-white, round, film-coated tablets with WPI over 3385 in bottles of 60 tablets (NDC 0591-3542-60).
Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room Temperature].
Dispense in a tight, light-resistant container as defined in the USP.
Manufactured by: Watson Laboratories, Inc.
Corona, CA 92880 USA Distributed by: Watson Pharma, Inc.
Corona, CA 92880 USA Issued: August 2010 172395-2
GERIATRIC USE
Geriatric Use: Of the approximately 6,000 patients who participated in clinical trials with bupropion sustained-release tablets (depression and smoking cessation studies), 275 were 65 and over and 47 were 75 and over.
In addition, several hundred patients 65 and over participated in clinical trials using the immediate-release formulation of bupropion (depression studies).
No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects; however, another pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites (see CLINICAL PHARMACOLOGY ).
Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and excreted by the kidneys.
The risk of toxic reaction to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see PRECAUTIONS: Renal Impairment and DOSAGE AND ADMINISTRATION ).
INDICATIONS AND USAGE
Bupropion hydrochloride extended-release tablets (SR) are indicated for the treatment of major depressive disorder.
The efficacy of bupropion in the treatment of a major depressive episode was established in two 4-week controlled trials of depressed inpatients and in one 6-week controlled trial of depressed outpatients whose diagnoses corresponded most closely to the Major Depression category of the APA Diagnostic and Statistical Manual (DSM) (see CLINICAL PHARMACOLOGY ).
A major depressive episode (DSM-IV) implies the presence of 1) depressed mood or 2) loss of interest or pleasure; in addition, at least 5 of the following symptoms have been present during the same 2-week period and represent a change from previous functioning: depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation.
The efficacy of bupropion in maintaining an antidepressant response for up to 44 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial (see CLINICAL PHARMACOLOGY ).
Nevertheless, the physician who elects to use bupropion hydrochloride extended-release tablets (SR) for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.
PEDIATRIC USE
Pediatric Use: Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS: Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders ).
Anyone considering the use of bupropion in a child or adolescent must balance the potential risks with the clinical need.
PREGNANCY
Pregnancy: Teratogenic Effects: Pregnancy Category C.
In studies conducted in rats and rabbits, bupropion was administered orally at doses up to 450 and 150 mg/kg/day, respectively (approximately 11 and 7 times the maximum recommended human dose [MRHD], respectively, on a mg/m 2 basis), during the period of organogenesis.
No clear evidence of teratogenic activity was found in either species; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day, approximately equal to the MRHD on a mg/m 2 basis) and greater.
Decreased fetal weights were seen at 50 mg/kg and greater.
When rats were administered bupropion at oral doses of up to 300 mg/kg/day (approximately 7 times the MRHD on a mg/m 2 basis) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development.
One study has been conducted in pregnant women.
This retrospective, managed-care database study assessed the risk of congenital malformations overall, and cardiovascular malformations specifically, following exposure to bupropion in the first trimester compared to the risk of these malformations following exposure to other antidepressants in the first trimester and bupropion outside of the first trimester.
This study included 7,005 infants with antidepressant exposure during pregnancy, 1,213 of whom were exposed to bupropion in the first trimester.
The study showed no greater risk for congenital malformations overall, or cardiovascular malformations specifically, following first trimester bupropion exposure compared to exposure to all other antidepressants in the first trimester, or bupropion outside of the first trimester.
The results of this study have not been corroborated.
Bupropion hydrochloride extended-release tablets (SR) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
NUSRING MOTHERS
Nursing Mothers: Like many other drugs, bupropion and its metabolites are secreted in human milk.
Because of the potential for serious adverse reactions in nursing infants from bupropion hydrochloride extended-release tablets (SR), a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
BOXED WARNING
WARNING Suicidality and Antidepressant Drugs Use in Treating Psychiatric Disorders : Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders.
Anyone considering the use of bupropion hydrochloride extended-release tablets (SR) or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need.
Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older.
Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide.
Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior.
Families and caregivers should be advised of the need for close observation and communication with the prescriber.
Bupropion hydrochloride extended-release tablets (SR) are not approved for use in pediatric patients.
(See WARNINGS: Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders , PRECAUTIONS: Information for Patients , and PRECAUTIONS: Pediatric Use ).
Use in Smoking Cessation Treatment: Wellbutrin®*, bupropion hydrochloride extended-release tablets (SR), and Wellbutrin XL®* are not approved for smoking cessation treatment, but bupropion under the name Zyban®* is approved for this use.
Serious neuropsychiatric events, including but not limited to depression, suicidal ideation, suicide attempt, and completed suicide have been reported in patients taking bupropion for smoking cessation.
Some cases may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking.
Depressed mood may be a symptom of nicotine withdrawal.
Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication.
However, some of these symptoms have occurred in patients taking bupropion who continued to smoke.
All patients being treated with bupropion for smoking cessation treatment should be observed for neuropsychiatric symptoms including changes in behavior, hostility, agitation, depressed mood, and suicide-related events, including ideation, behavior, and attempted suicide.
These symptoms, as well as worsening of pre-existing psychiatric illness and completed suicide have been reported in some patients attempting to quit smoking while taking Zyban®* in the postmarketing experience.
When symptoms were reported, most were during treatment with Zyban®*, but some were following discontinuation of treatment with Zyban®*.
These events have occurred in patients with and without pre-existing psychiatric disease; some have experienced worsening of their psychiatric illnesses.
Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major depressive disorder did not participate in the premarketing studies of Zyban®*.
Advise patients and caregivers that the patient using bupropion for smoking cessation should stop taking bupropion and contact a healthcare provider immediately if agitation, hostility, depressed mood, or changes in thinking or behavior that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior.
In many postmarketing cases, resolution of symptoms after discontinuation of Zyban®* was reported, although in some cases the symptoms persisted; therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.
The risks of using bupropion for smoking cessation should be weighed against the benefits of its use.
Zyban®* has been demonstrated to increase the likelihood of abstinence from smoking for as long as 6 months compared to treatment with placebo.
The health benefits of quitting smoking are immediate and substantial.
(See WARNINGS: Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment and PRECAUTIONS: Information for Patients .)
INFORMATION FOR PATIENTS
Information for Patients: Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with bupropion hydrochloride extended-release tablets (SR) and should counsel them in its appropriate use.
A patient Medication Guide about “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions” “Quitting Smoking, Quit-Smoking Medication, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or Actions,” and “What Other Important Information Should I Know About bupropion hydrochloride extended-release tablets (SR)?” is available for bupropion hydrochloride extended-release tablets (SR).
The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents.
Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have.
The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking bupropion hydrochloride extended-release tablets (SR).
Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders : Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down.
Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt.
Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment: Although bupropion hydrochloride extended-release tablets (SR) are not indicated for smoking cessation treatment, it contains the same active ingredient as Zyban®* which is approved for this use.
Patients should be informed that quitting smoking, with or without Zyban®*, may be associated with nicotine withdrawal symptoms (including depression or agitation), or exacerbation of pre-existing psychiatric illness.
Furthermore, some patients have experienced changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide when attempting to quit smoking while taking Zyban®*.
If patients develop agitation, hostility, depressed mood, or changes in thinking or behavior that are not typical for them, or if patients develop suicidal ideation or behavior, they should be urged to report these symptoms to their healthcare provider immediately.
Bupropion-Containing Products: Patients should be made aware that bupropion hydrochloride extended-release tablets (SR) contain the same active ingredient found in Zyban ®* , used as an aid to smoking cessation treatment, and that bupropion hydrochloride extended-release tablets should not be used in combination with Zyban ®* or any other medications that contain bupropion hydrochloride (such as Wellbutrin ®* , the immediate-release formulation and Wellbutrin XL ®* , the extended-release formulation).
As dose is increased during initial titration to doses above 150 mg/day, patients should be instructed to take bupropion hydrochloride extended-release tablets (SR) in 2 divided doses, preferably with at least 8 hours between successive doses, to minimize the risk of seizures.
Patients should be told that bupropion hydrochloride extended-release tablets (SR) should be discontinued and not restarted if they experience a seizure while on treatment.
Patients should be told that any CNS-active drug like bupropion hydrochloride extended-release tablets (SR) may impair their ability to perform tasks requiring judgment or motor and cognitive skills.
Consequently, until they are reasonably certain that bupropion hydrochloride extended-release tablets (SR) do not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.
Patients should be told that the excessive use or abrupt discontinuation of alcohol or sedatives (including benzodiazepines) may alter the seizure threshold.
Some patients have reported lower alcohol tolerance during treatment with bupropion hydrochloride extended-release tablets (SR).
Patients should be advised that the consumption of alcohol should be minimized or avoided.
Patients should be advised to inform their physicians if they are taking or plan to take any prescription or over-the-counter drugs.
Concern is warranted because bupropion hydrochloride extended-release tablets (SR) and other drugs may affect each other’s metabolism.
Patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy.
Patients should be advised to swallow bupropion hydrochloride extended-release tablets (SR) whole so that the release rate is not altered.
Do not chew, divide, or crush tablets, as this may lead to an increased risk of adverse effects, including seizures.
DOSAGE AND ADMINISTRATION
General Dosing Considerations: It is particularly important to administer bupropion hydrochloride extended-release tablets (SR) in a manner most likely to minimize the risk of seizure (see WARNINGS ).
Gradual escalation in dosage is also important if agitation, motor restlessness, and insomnia, often seen during the initial days of treatment, are to be minimized.
If necessary, these effects may be managed by temporary reduction of dose or the short-term administration of an intermediate to long-acting sedative hypnotic.
A sedative hypnotic usually is not required beyond the first week of treatment.
Insomnia may also be minimized by avoiding bedtime doses.
If distressing, untoward effects supervene, dose escalation should be stopped.
Bupropion hydrochloride extended-release tablets (SR) should be swallowed whole and not crushed, divided, or chewed, as this may lead to increased risk of adverse effects including seizures.
Initial Treatment: The usual adult target dose for bupropion hydrochloride extended-release tablets (SR) is 300 mg/day, given as 150 mg twice daily.
Dosing with bupropion hydrochloride extended-release tablets (SR) should begin at 150 mg/day given as a single daily dose in the morning.
If the 150 mg initial dose is adequately tolerated, an increase to the 300 mg/day target dose, given as 150 mg twice daily, may be made as early as day 4 of dosing.
There should be an interval of at least 8 hours between successive doses.
Increasing the Dosage Above 300 mg/day: As with other antidepressants, the full antidepressant effect of bupropion hydrochloride extended-release tablets (SR) may not be evident until 4 weeks of treatment or longer.
An increase in dosage to the maximum of 400 mg/day, given as 200 mg twice daily, may be considered for patients in whom no clinical improvement is noted after several weeks of treatment at 300 mg/day.
Maintenance Treatment: It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacological therapy beyond response to the acute episode.
In a study in which patients with major depressive disorder, recurrent type, who had responded during 8 weeks of acute treatment with bupropion hydrochloride extended-release tablets (SR) were assigned randomly to placebo or to the same dose of bupropion hydrochloride extended-release tablets (SR) (150 mg twice daily) during 44 weeks of maintenance treatment as they had received during the acute stabilization phase, longer-term efficacy was demonstrated (see CLINICAL TRIALS under CLINICAL PHARMACOLOGY ).
Based on these limited data, it is unknown whether or not the dose of bupropion hydrochloride extended-release tablets (SR) needed for maintenance treatment is identical to the dose needed to achieve an initial response.
Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment.
Dosage Adjustment for Patients with Impaired Hepatic Function: Bupropion hydrochloride extended-release tablets (SR) should be used with extreme caution in patients with severe hepatic cirrhosis.
The dose should not exceed 100 mg every day or 150 mg every other day in these patients.
Bupropion hydrochloride extended-release tablets (SR) should be used with caution in patients with hepatic impairment (including mild-to-moderate hepatic cirrhosis) and a reduced frequency and/or dose should be considered in patients with mild-to-moderate hepatic cirrhosis (see CLINICAL PHARMACOLOGY , WARNINGS , and PRECAUTIONS ).
Dosage Adjustment for Patients with Impaired Renal Function: Bupropion hydrochloride extended-release tablets (SR) should be used with caution in patients with renal impairment and a reduced frequency and/or dose should be considered (see CLINICAL PHARMACOLOGY and PRECAUTIONS ).